Parenchymal injury in remnant-kidney model may be linked to apoptosis of renal cells mediated by nitric oxide.
BACKGROUND
The importance of apoptotic cell death in the pathogenesis of progressive renal sclerosis has been well established. While activity of vasorelaxant nitric oxide is conceivable in the remnant hyperfiltrating kidney and nitric oxide has been reported to cause apoptosis, we postulated that this mechanism of cell death may be operating in progressive renal fibrosis.


METHODS
The intensity of apoptosis in glomerular and tubular cells was assessed (light microscopy, TUNEL method) in the remnant-kidney model of progressive renal fibrosis in rats undergoing 5/6 nephrectomy. Numbers of apoptotic cells were correlated with expression of mRNA for inducible nitric oxide synthase (iNOS; RT-PCR in situ), generation of nitrite in renal tissue, an index of glomerulosclerosis, proteinuria and creatinine clearance. A control group of 5/6 nephrectomized rats received an iNOS inhibitor, L-NAME, in drinking water during the 4 weeks after nephrectomy.


RESULTS
Number of apoptotic cells gradually increased in experimental rats both in glomeruli and tubules, until termination of the study 3 months after 5/6 nephrectomy. At 3 months postinduction, the intensity of tubular cell apoptosis was significantly correlated with creatinine clearance (p<0.05), while glomerular cell apoptosis was correlated with the index of glomerulosclerosis, also at 3 months (p<0.0025). Along with the apoptosis, the levels of iNOS mRNA for, and generation of, nitrite in renal tissue had risen until termination of the study. The generation of nitrites correlated with the number of apoptotic glomerular cells (p<0.025). Treatment with the iNOS inhibitor resulted in a significant reduction in number of apoptotic cells (p<0.01).


CONCLUSIONS
Apoptotic depletion of renal tubular and glomerular cells linked to activity of iNOS may contribute to progression of chronic kidney tissue injury in the 5/6 nephrectomy model.
Hruby
Zbigniew
Z
Department of Nephrology, Wroclaw Medical University, Wroclaw - Poland. hruby@wssk.wroc.pl
Rosinski
Maciej
M
Tyran
Bronislaw
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020287:In Situ Nick-End Labeling; D007672:Kidney Cortex / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D009400:Nephrosclerosis / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D009573:Nitrites; D012333:RNA, Messenger; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II